The tumor suppressor PTEN is a dual-specificity phosphatase (lipid and protein) that functions as a check (or the “brakes”) on the PI3K signaling complex. PTEN mediates the dephosphorylation of phosphatidylinositol-triphosphate (PIP3) to phosphatidylinositol-diphosphate (PIP2), eliminating the membrane binding site for 3-Phosphoinositide-Dependent Kinase-1 (PDK1) and Akt/protein kinase B (PKB) and thus antagonizing the activity of PI3K. The PTEN gene (at locus 10q23) is inactivated in a number of human malignancies, including breast, brain, endometrial, kidney, and prostate cancers. The inactivation of PTEN correlates with disease progression and poor prognosis, suggesting a key role in oncogenesis (Bose S, et al (2002) Reduced expression of PTEN correlates with breast cancer progression. Hum. Pathol. 33:405-409; Rubin M A, et al (2000) 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer, Hum. Pathol. 31:504-508, and Depowski P L, Rosenthal S I, Ross J S (2001) Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod. Pathol. 14:672-676).
In experimental systems, inactivation of PTEN has been shown to lead to unchecked activation of Akt/PKB. Unchecked Akt/PKB activity leads to inhibition of apoptosis, cellular growth, and enhanced proliferation, and subsequently to an oncogenic phenotype. Restoration of PTEN expression in PTEN-null systems leads to loss of the oncogenic phenotype.
In breast cancer, multiple mechanisms of PTEN loss of function have been demonstrated, including mutations, gene deletions, and transcriptional downregulation via miRNA or epigenetic silencing. Most of these mechanisms of inactivation lead to a significant reduction in the amount of the PTEN protein that is produced in the tumor cells. In tumors harboring such mechanisms of inactivation, a reduction in PTEN protein levels in breast cancer has been observed using various protein measurements, including one standard method used in diagnostics, immunohistochemistry (IHC). Using IHC, various studies have reported reduced PTEN in 15% to 48% of patients. The spectrum of PTEN mutations, gene deletions, and epigenetic events as mechanisms of inactivation present an interesting study of tumor biology, and the variable combinations of these inactivation mechanisms are likely to contribute to the heterogeneity in published literature on the reduction in PTEN expression observed. Mutations in the PTEN gene are quite common in malignancies, such as endometrial carcinoma and glioblastoma; however, such mutations are relatively rare in breast cancer. Mutations in the PTEN gene are found in approximately 5% of patients and most represent frame shift mutations that can lead to a destabilized protein. In contrast, the major mechanism of PTEN inactivation in breast cancer appears to be PTEN gene deletion. Multiple additional mechanisms of PTEN loss beyond gene loss or mutations have been identified. At the transcriptional level, epigenetic silencing via promoter methylation or miRNA expression (e.g., miR-21) have been described. Further mechanisms to reduce PTEN expression involve loss of stabilizing proteins, such as Rak, which phosphorylates PTEN, thus protecting it from ubiquitin-mediated degradation.
Multiple approaches to PTEN IHC have been published with the attempt to correlate to drug response (See for example, Berns K et al. (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer; Cancer Cell 12:395-402; and Nagata Y et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients; Cancer Cell 6:117-127).